In 1999, 61% of adults, 13% of children aged 6 to 11 years and 14% of adolescents aged 12 to 19 years in the United States were overweight. Increases in occurrence of overweight and obesity has been seen in all age, racial and ethnic groups, and in both men and women.
Epidemiological studies show an increase in mortality associated with overweight and obesity. Individuals who are obese (body mass index (“BMI”)>30) have a 50-100% increased risk of premature death from all causes compared to individuals with a BMI in the range of 20 to 25. BMI is calculated according to the formula:
  BMI  =                    Weight        ⁢                                  ⁢        in        ⁢                                  ⁢        pounds                              (                      Height            ⁢                                                  ⁢            in            ⁢                                                  ⁢            inches                    )                2              ×    703  
An estimated 300,000 deaths a year in the United States may be attributable to obesity. Overweight and obesity are associated with an increased risk for coronary heart disease; type 2 diabetes; endometrial, colon, postmenopausal breast, and other cancers; and certain musculoskeletal disorders, such as knee osteoarthritis.
Both modest and large weight gains are associated with significantly increased risk of disease. For example, a weight gain of 11 to 18 pounds increases a person's risk of developing type 2 diabetes to twice that of individuals who have not gained weight, while those who gain 44 pounds or more have four times the risk of type 2 diabetes. A gain of approximately 10 to 20 pounds results in an increased risk of coronary heart disease (nonfatal myocardial infarction and death) of 1.25 times in women and 1.6 times in men. Higher levels of body weight gain of 22 pounds in men and 44 pounds in women result in an increased coronary heart disease risk of 1.75 and 2.65, respectively. In women with a BMI of 34 or greater, the risk of developing endometrial cancer is increased by more than six times. Overweight and obesity are also known to exacerbate many chronic conditions such as hypertension and elevated cholesterol. Overweight and obese individuals also may suffer from social stigmatization, discrimination, and poor body image. Although obesity-associated morbidities occur most frequently in adults, important consequences of excess weight as well as antecedents of adult disease occur in overweight children and adolescents. Overweight children and adolescents are more likely to become overweight or obese adults; this concern is greatest among adolescents. Type 2 diabetes, high blood lipids, and hypertension as well as early maturation and orthopedic problems also occur with increased frequency in overweight youth. A common consequence of childhood overweight is psychosocial-specifically discrimination. See The Surgeon General's Call To Action To Prevent and Decrease Overweight and Obesity, U.S. Dept. of Health and Human Services, 2001. Thus, the need exists for methods of controlling weight and treating obesity.
Melanin-concentrating hormone (MCH) is a cyclic, 19-amino acid hypothalamic neuropeptide derived from a larger pro-hormone precursor of MCH, Pmch. Pmch-deficient mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice over-expressing Pmch are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis, through actions on motor activity, metabolism, food intake and neuroendocrine function.
Two receptors have been identified in MCH, and are designated MCH 1 receptor and MCH 2 receptor. The MCH 1 and MCH 2 receptors are G protein-coupled receptors (GPCRs) believed to be responsible for the actions of MCH. G proteins are heterotrimeric proteins that control cellular responses to stimuli by cycling between a GTP-bound active state, which regulates the activity of a number of effector proteins, and a GDP-bound inactive state. GPCRs accelerate activation of the G protein by increasing the GDP/GTP exchange rate.
MCH 1 receptor-deficient mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly, MCH 1 receptor-deficient mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, MCH 1 receptor-deficient mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in MCH 1 receptor-deficient mice. Marsh et al., Proc. Nat. Acad. Sci., 99(5), 3241 (2002).
Because MCH has been shown to be an important regulator of food intake and energy balance, compounds capable of modulating the activity of MCH receptors, particularly MCH 1 receptors, are highly desirable for the treatment of eating disorders and metabolic disorders.
PCT Publication No. WO 02/04433 describes phenylcycloalkylmethylamino and phenylalkenylamino derivatives as modulators of MCH 1 receptors useful in the treatment of certain metabolic, feeding and sexual disorders.
U.S. Pat. No. 6,472,394 describes the use of amide derivatives of 1,4-disubstituted piperidine as MCH antagonists for the treatment of obesity and diabetes.